Visceral leishmaniasis is a worldwide health problem and is highly endemic in northeastern Brazil in the states of Rio Grande do Norte, Ceara and Bahia. It is typically caused by Leishmania chagasi, an intracellular protozoal pathogen of mammalian macrophages, which is transmitted by the sandfly, Lutzomyia longipalpis. Studies in rural endemic areas of Ceara indicate that approximately 5% of young children are infected each year. Of these, 1 in 8 develops progressive visceral leishmaniasis, which carries a mortality rate approaching 10%. The rest develop leishmania- specific CD4+ Th1 responses and have self-resolving infections. There is currently no effective form of immunoprophylaxis against L. chagasi and standard treatment of visceral leishmaniasis with glucantime, a pentavalent antimonial, is variably effective and frequently associated with toxicity. An accurate understanding of the immunobiology of human L. chagasi infection and identification of leishmanial antigens that elicit protective T cell responses are necessary if we are to develop an effective approach to immunoprophylaxis. Three central hypotheses that are critical to this end will be tested: (1) that L. chagasi-infected persons who exhibit Th1 responses as evidenced by secretion of interferon- gamma and interleukin-2 after self-resolving infection or successful treatment of progressive visceral leishmaniasis have long standing immunity that protects them against visceral leishmaniasis; (2) that L. chagasi antigens of 46 kDa, 41 kDa and 40 kDa are capable of eliciting potentially protective Th1 responses in individuals who have had self- resolving infection or who have undergone successful chemotherapy; and (3) that the susceptibility of humans to progressive visceral leishmaniasis is mediated by specific polymorphic alleles of the human Nramp gene and distinct HLA haplotype(s). The availability of a large number of L. chagasi-infected persons in both a well defined rural study area in the state of Ceara and in close proximity to research facilities in the city of Natal, Rio Grande do Norte, provides a unique opportunity to test these hypotheses. Completion of the proposed studies will provide data critical to the development of an effective approach to immunoprophylaxis for residents of northeastern Brazil and other endemic areas.